RESUMEN

The wound healing that follows myocardial infarction is a complex process involving multiple mechanisms, such as inflammation, angiogenesis and fibrosis. In the last two decades, the involvement of WNT signaling has been extensively studied and effects on virtually all aspects of this wound healing have been reported. However, as often is the case in a newly emerging field, inconsistent and sometimes even contradictory findings have been reported. The aim of this systematic review is to provide a comprehensive overview of studies in which the effect of interventions in WNT signaling were investigated in in vivo models of cardiac injury. To this end, we used different search engines to perform a systematic search of the literature using the key words "WNT and myocardial and infarction". We categorized the interventions according to their place in the WNT signaling pathway (ligand, receptor, destruction complex or nuclear level). The most consistent improvements of the wound healing response were observed in studies in which the acylation of WNT proteins was inhibited by administering porcupine inhibitors, by inhibiting of the downstream glycogen synthase kinase-3ß (GSK3ß) and by intervening in the ß-catenin-mediated gene transcription. Interestingly, in several of these studies, evidence was presented for activation of cardiomyocyte proliferation around the infarct area. These findings indicate that inhibition of WNT signaling can play a valuable role in the repair of cardiac injury, thereby improving cardiac function and preventing the development of heart failure.

Asunto(s)

Miocardio/patología , Vía de Señalización Wnt , Cicatrización de Heridas , Animales , Apoptosis , Humanos , Inflamación/patología , Miocitos Cardíacos/patología , Neovascularización Fisiológica

RESUMEN

BACKGROUND: The inflammatory response due to myocardial tissue injury in the setting of acute ST-elevation myocardial infarction (STEMI) is essential for proper local infarct healing. However, an excessive inflammatory response may aggravate myocardial damage and hampers infarct healing processes. The present study aimed to investigate the association of systemic inflammatory biomarkers with infarct size (IS) dynamics post-STEMI, using cardiac magnetic resonance (CMR) imaging. METHODS: This prospective observational study included 245 STEMI patients treated with primary percutaneous coronary intervention (pPCI). Peak values of high-sensitivity C-reactive protein (hs-CRP), white blood cell count (WBCc) and fibrinogen were determined serially until 96 h after pPCI. Infarct healing, defined as relative IS reduction from baseline to 4 months after STEMI, was assessed using late gadolinium enhanced CMR imaging. RESULTS: IS significantly decreased from 16% of left ventricular mass (LVM) (Interquartile range [IQR]:8-24) at baseline to 10% (IQR:5-17) at 4 months (p < 0.001). Relative IS reduction was 35% (IQR:8-50). Whereas peak WBCc (p = 0.926) and peak fibrinogen (p = 0.161) were not significantly associated with relative IS reduction, peak hs-CRP showed a significant association with IS reduction (p = 0.003). In multivariable logistic regression analysis, the association between peak hs-CRP and relative IS reduction remained significant after adjustment for baseline IS, hypertension, hs-cardiac troponin T and N-terminal pro B-type natriuretic peptide (odds ratio:0.35 [95% confidence interval:0.19-0.63]; p = 0.001). CONCLUSIONS: In STEMI patients treated with pPCI, hs-CRP was independently associated with 4 months IS reduction as determined by CMR, suggesting a pathophysiological interplay between inflammation and adverse infarct healing in survivors of acute STEMI.

Asunto(s)

Infarto de la Pared Anterior del Miocardio , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Biomarcadores , Proteína C-Reactiva , Humanos , Miocardio , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/cirugía

RESUMEN

Despite early revascularization, remodeling and dysfunction of the left ventricle (LV) after acute myocardial infarction (AMI) remain important therapeutic targets. Intermittent pacing therapy (IPT) of the LV can limit infarct size, when applied during early reperfusion. However, the effects of IPT on post-AMI LV remodeling and infarct healing are unknown. We therefore investigated the effects of IPT on global LV remodeling and infarct geometry in swine with a 3-day old AMI. For this purpose, fifteen pigs underwent 2 h ligation of the left circumflex coronary artery followed by reperfusion. An epicardial pacing lead was implanted in the peri-infarct zone. After three days, global LV remodeling and infarct geometry were assessed using magnetic resonance imaging (MRI). Animals were stratified into MI control and IPT groups. Thirty-five days post-AMI, follow-up MRI was obtained and myofibroblast content, markers of extracellular matrix (ECM) turnover and Wnt/frizzled signaling in infarct and non-infarct control tissue were studied. Results showed that IPT had no significant effect on global LV remodeling, function or infarct mass, but modulated infarct healing. In MI control pigs, infarct mass reduction was principally due to a 26.2 ± 4.4% reduction in infarct thickness (P ≤ 0.05), whereas in IPT pigs it was mainly due to a 35.7 ± 4.5% decrease in the number of infarct segments (P ≤ 0.05), with no significant change in infarct thickness. Myofibroblast content of the infarct zone was higher in IPT (10.9 ± 2.1%) compared to MI control (5.4 ± 1.6%; P ≤ 0.05). Higher myofibroblast presence did not coincide with alterations in expression of genes involved in ECM turnover or Wnt/frizzled signaling at 5 weeks follow-up. Taken together, IPT limited infarct expansion and altered infarct composition, showing that IPT influences remodeling of the infarct zone, likely by increasing regional myofibroblast content.

Asunto(s)

Estimulación Cardíaca Artificial/métodos , Infarto del Miocardio/patología , Remodelación Ventricular , Animales , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética , Masculino , Reacción en Cadena de la Polimerasa , Distribución Aleatoria , Porcinos

RESUMEN

Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type-specific regulation of Fstl1 and its function in a murine model of MI Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area compared to cardiac myocytes. The conditional ablation of Fstl1 in S100a4-expressing fibroblast lineage cells (Fstl1-cfKO mice) led to a reduction in injury-induced Fstl1 expression and increased mortality due to cardiac rupture during the acute phase. Cardiac rupture was associated with a diminished number of myofibroblasts and decreased expression of extracellular matrix proteins. The infarcts of Fstl1-cfKO mice displayed weaker birefringence, indicative of thin and loosely packed collagen. Mechanistically, the migratory and proliferative capabilities of cardiac fibroblasts were attenuated by endogenous Fstl1 ablation. The activation of cardiac fibroblasts by Fstl1 was mediated by ERK1/2 but not Smad2/3 signaling. This study reveals that Fstl1 is essential for the acute repair of the infarcted myocardium and that stimulation of early fibroblast activation is a novel function of Fstl1.

Asunto(s)

Fibroblastos/fisiología , Proteínas Relacionadas con la Folistatina/metabolismo , Infarto del Miocardio/complicaciones , Infarto del Miocardio/patología , Rotura/patología , Animales , Modelos Animales de Enfermedad , Endopeptidasas , Folistatina , Proteínas Relacionadas con la Folistatina/deficiencia , Gelatinasas , Proteínas de la Membrana , Ratones , Ratones Noqueados , Serina Endopeptidasas , Análisis de Supervivencia

RESUMEN

PURPOSE: To provide direct evidence that mechanical obstruction of microvessels inhibits infarct resorption (healing) and enhances left ventricular (LV) remodeling using MRI. MATERIALS AND METHODS: Animals (n = 20 pigs) served as controls (group I) or were subjected to either 90 min left anterior descending (LAD) coronary artery occlusion/reperfusion (group II) or 90 min LAD occlusion/ microemboli delivery/reperfusion (group III). MRI (cine and delayed contrast enhanced MRI, DE-MRI) was performed at 3 days and 5 weeks after interventions and used for assessing LV function, mass, and extent of myocardial damage and microvascular obstruction (MVO) using semi-automated threshold method. RESULTS: Persistent MVO in the core of contiguous infarct was larger and more frequent (n = 8/8) in group III than group II (4/8) on DE-MRI at 3 days. Furthermore, patchy microinfarct, as a result of microembolization, was visible as hyperenhanced zone at the borders of the contiguous infarct. The reduction in ejection fraction and increase in LV volumes on cine MRI were greater in group III than group II at 3 days and 5 weeks, which may be attributed to the slow infarct resorption, MVO extents and patchy microinfarct at the borders. CONCLUSION: This MRI study illustrates the recently raised conjecture that MVO delays/inhibits infarct resorption (healing), accentuates LV hypertrophy and pathological remodeling.

Asunto(s)

Circulación Coronaria , Hipertrofia Ventricular Izquierda/fisiopatología , Imagen por Resonancia Cinemagnética/métodos , Microvasos/fisiopatología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Remodelación Ventricular/fisiología , Animales , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/patología , Microvasos/patología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/complicaciones , Daño por Reperfusión Miocárdica/patología , Recuperación de la Función , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Porcinos

RESUMEN

Following a myocardial infarction (MI), fibroblasts differentiate to myofibroblasts, which possess some of the characteristics of smooth muscle cells (SMCs) and contribute to wound healing. Previous studies suggested that the miR-143/-145 cluster plays a critical role in SMC differentiation. Therefore, we determined whether miR-145 promoted differentiation of cardiac fibroblasts to myofibroblasts. Following coronary occlusion in mice, myocardial miR-145 expression was downregulated at 3 days but was restored at 7 days. In vitro studies showed that hypoxia also downregulated miR-145 in cardiac fibroblasts. The number of α-smooth muscle actin (α-SMA) positive cells in fibroblast cultures was employed to determine their transdifferentiation to cardiac myofibroblasts and was increased by 73.5% after transient transfection with miR-145. Ultrastructural analysis of α-SMA stress fibers revealed that ~95% of the α-SMA(+) cells treated with miR-145 organized their actin-filament bundles with a specific orientation compared to only 15% in the scrambled control group. This orientation of the SMA bundles and their integration with the filamentous actin fibers of the cytoskeleton permit infarct wound contraction. Structural and functional studies showed that miR-145 induced a myofibroblast phenotype, and miR-145 also potentiated the production of mature collagen by myofibroblasts. Repression of KLF5, a target of miR-145, was validated by a chimeric luciferase construct tagged with the full-length 3'-UTR of KLF5. A dramatic decrease in KLF5 and a corresponding increase in myocardin expression were observed after transfecting cultured fibroblasts with miR-145. Similar results were found in vivo: the transient decrease in miR-145 expression 3 days post-MI was associated with an increase in KLF5 and a decrease in myocardin. In addition, in vivo delivery of a miR-145 antagomir 1 day prior to and 2 and 6 days after MI decreased myofibroblast formation and increased scar size. The antagomir also reversed the suppressed expression of KLF5 protein in the scar region at day 7 after MI. In summary, we describe a novel association between miR-145 and fibroblast differentiation toward myofibroblasts. These observations provide a new approach to promote endogenous scar healing and contracture by stimulating the transdifferentiation of cardiac fibroblasts to myofibroblasts.

Asunto(s)

Fibroblastos/metabolismo , MicroARNs/genética , Miocardio/metabolismo , Repitelización/fisiología , Actinas/genética , Actinas/metabolismo , Animales , Diferenciación Celular , Transdiferenciación Celular , Colágeno/genética , Colágeno/metabolismo , Oclusión Coronaria/patología , Vasos Coronarios/cirugía , Femenino , Fibroblastos/patología , Expresión Génica , Genes Reporteros , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Miocardio/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligonucleótidos Antisentido/genética , Transactivadores/genética , Transactivadores/metabolismo